Tuberculosis (TB) remains a serious threat to global health. The discovery of 1,3-benzothiazin-4-ones (BTZs), especially BTZ043 and PBTZ-169 (FIG. 1) as impressively potent and selective agents for the treatment of tuberculosis (TB), prompted highly intensive research in the area of electron deficient nitroaromatic warheads as anti-TB agents.
Prior to the discovery of BTZs, several nitroaromatic compounds were found to have interesting anti-TB activity, especially PA-824, OPC67683, nitrofuranylamides and nitrofuran isooxazolines. The mode of activation of BTZ and related compounds has been shown to involve reduction of the essential nitro group to a reactive nitroso moiety 3, which then reacts with cysteine 387 of DprE1 to form a covalent, semimercaptal adduct, 4 (FIG. 2). Subsequently, several other related electron deficient aromatic compounds have been shown to cause similar covalent inhibition of DprE1, including dinitrobenzamides (e.g. DNB1), benzoquinoxalines (e.g. VI-9376) and nitrosubstituted triazoles (e.g. 377790). Recently, the present inventors' work related to the metabolic activation of BTZ043 and other nitroaromatic agents revealed that the key nitroso intermediate (i.e. 3) can also be generated by nucleophilic cine addition of thiolates or possibly hydrides. In the absence of the enzyme, azoxy and related nitroso derived dimers were generated and characterized. The present inventors also reported that further reduction produces the corresponding inactive hydroxylamine and amine. Makarov et al, recently also demonstrated that both compounds 1 and 2 undergo reduction in the presence of purified nitro reductase to the corresponding hydroxylamine and azoxy analogues. Thus, BTZ and other electrophilic nitroaromatic anti-TB compounds are susceptible to redox activation both in vitro and in vivo.
Discussions in the literature on nitroaromatic anti-TB warheads related to BTZ043 have mostly been focused on the reductive metabolism catalyzed either by DprE1 or nitroreductases. A potential alternative metabolic fate involves oxidative processes. S-Oxidation of sulfur-containing therapeutics is a well-known metabolic transformation catalyzed by cytochrome P450s or by flavin monoxygenases.